IDENTIFICATION OF THE CLINICAL FEATURES DISTINGUISHING PSORIATIC ARTHRITIS AND FIBROMYALGIA

Identification of the Clinical Features Distinguishing Psoriatic Arthritis and FibromyalgiaThis is a repository copy of Identification of the Clinical Features Distinguishing Psoriatic Arthritis and Fibromyalgia.
White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/140530/
Version: Accepted Version
Article:
Marchesoni, A, Atzeni, F, Spadaro, A et al. (18 more authors) (2012) Identification of the Clinical Features Distinguishing Psoriatic Arthritis and Fibromyalgia. The Journal of Rheumatology, 39 (4). pp. 849-855. ISSN 0315-162X
https://doi.org/10.3899/jrheum.110893
The Journal of Rheumatology Copyright © 2012. All rights reserved. This is an author produced version of an article published in the Journal of Rheumatology. Uploaded in accordance with the publisher's self-archiving policy.
[email protected] https://eprints.whiterose.ac.uk/
Reuse
Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item.
Takedown
If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request.
ARTHRITIS AND FIBROMYALGIA
Provenzano5, Alberto Cauli6, Olivieri Ignazio7, Daniela Melchiorre8, Carlo Salvarani9,
Raffaele Scarpa10, Piercarlo Sarzi-Puttini2, Monica Montepaone3, Giovanni Porru6,
Salvatore D’Angelo7, Mariagrazia Catanoso9, Luisa Costa10, Maria Manara1, Valentina
Varisco2, Laura Rotunno1, Orazio De Lucia11, Gabriele De Marco1.
Institutions 1. U.O.C. Day Hospital Reumatologia, Istituto Ortopedico G. Pini, Milano, Italy
2. Unità di Reumatologia, Ospedale L.Sacco, Polo Universitario, Milano and Centre for
Experimental Medicine and Rheumatology, William Harvey Research Institute ,
London, UK
3. Dipartimento di Medicina Interna e Specialità Mediche, Reumatologia, Sapienza
Università di Roma, Italy
4. Academic Rheumatology Unit, Department of Health Sciences, University of Molise,
Campobasso, Italy.
Palermo, Italy
6. Chair of Rheumatology, Department of Medical Sciences, University of Cagliari, Italy
7. Rheumatology Department of Lucania, San Carlo Hospital, Potenza and Madonna
delle Grazie Hospital, Matera, Italy
8. Department of Internal Medicine, Division of Rheumatology, University of Florence,
Italy
9. Unità di Reumatologia, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
10. Rheumatology Research Unit, University Federico II, Napoli,Italy
11. U.O.C. Divisione di Reumatologia, Istituto Ortopedico G. Pini, Milano, Italy
Page 2 of 24
Financial support This work has been carried out using local resources only and did not receive any external
support. None of the Authors has conflicts of interest regarding this work.
A Marchesoni, MD, F Atzeni, MD, A. Spadaro, Associate Professor of Rheumatology, E
Lubrano, Associate Professor of Rheumatology, G Provenzano, MD, A Cauli, MD, I
Olivieri, MD, D Melchiorre, MD, C Salvarani, MD, R Scarpa, MD, Associate Professor od
Rheumatology, P Sarzi Puttini, MD, M Montepaone, MD, G Porru, MD, S D’Angelo, MD, M
Catanoso, MD, L Costa, MD, M Manara, MD, V Varisco, MD, L Rotunno, MD, O De Lucia,
MD, G De Marco, MD
Author responsible for correspondence and reprints requests Antonio Marchesoni,
UOC Day Hospital of Rheumatology,
Istituto Ortopedico Gaetano Pini,
Piazza A. Ferrari 1,
Email: [email protected]
Key words: Psoriatic arthritis; fibromyalgia; pain; enthesitis
Page 3 of 24
ABSTRACT
Objective. The aim of this study was to identify the clinical features that can help to
distinguish between psoriatic arthritis (PsA) and fibromyalgia (FM).
Methods. This multicentre cross-sectional study was carried out in ten Italian
rheumatological centres between January and September 2009, and enrolled all of the
consecutive PsA and FM patients who agreed to participate. All of the standard clinical
and laboratory data for PsA and FM were collected from all of the patients, and their
somatic symptoms, response to non-steroidal anti-inflammatory drugs (NSAIDs), self-
evaluated pain, general health, disability and responses to the Fibromyalgia Impact
Questionnaire were recorded. The data were statistically analysed by means of univariate
and multivariate analyses, and receiver operating characteristic curves. Given the purpose
of the study, the analysis concentrated on the clinical features shared by the two
conditions.
Results. Two hundred and sixty-six PsA patients (mean age 51.7 years; disease duration
10.2 years) and 120 FM patients (mean age 50.2 years; disease duration 5.6 years) were
evaluated. Univariate analysis showed that the FM patients had higher mean tender point
and enthesitic scores, more somatic symptoms, and responded less to NSAIDs.
Multivariate analysis showed that the presence of 6 FM-associated symptoms and 8 or
more tender points were the best predictors of FM.
Conclusion. The shared clinical features of PsA and FM that had the greatest
discriminating power for FM were the number of FM-associated symptoms and tender
point count.
INTRODUCTION
Fibromyalgia (FM) is a common cause of chronic widespread pain (CWP) and often
responsible for rheumatologic consultations. Its prevalence in the general adult general
population is about 2%, but considerably different between males and females (about
0.5% vs about 3.5%) [1,2]. According to the 1990 ACR criteria [3], a diagnosis of FM
requires the presence of CWP and tenderness in at least 11 out of 18 tender points when
applying a pressure of 5 kg. A new set of criteria has recently been proposed by the ACR
[4] that does not require a tender point examination but includes a subjective measure of
the number of painful body regions and a somatic symptom severity scale. In association
with CWP, somatic symptoms such as fatigue, headache, irritable bowel syndrome, sleep
disturbances, paresthesias, muscle weakness, bladder dysfunction, depression, anxiety,
Raynaud’s phenomenon and many others are typical features of FM, and the constellation
of symptoms is such that the disease is usually easily recognised by physicians. However,
diagnostic difficulties may arise in case of CWP due to condition other than FM.
Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disorder belonging to
the heterogeneous group of spondyloarthropathies (SpAs), and can affect up to 30% of
patients with psoriasis [5]. It is a protean disease that involves the entheses, joints,
tendons and bones of both the peripheral and axial skeleton. Enthesitis can be very
difficult to diagnose because its symptoms and signs may be aspecific and relatively
indistinguishable from those of FM. Patients with primary FM and psoriasis or FM
associated with PsA and those with psoriatic polyenthesitis may have almost identical
clinical features and are at risk of misdiagnosis and management errors.
The aim of this study was to identify which clinical features recorded during a standard
rheumatological evaluation might help to distinguish PsA and FM.
Page 5 of 24
Study design
This multicentre, cross-sectional study was carried out by 10 Italian tertiary
rheumatological centres between January and September 2009: seven Centres
specialised in PsA enrolled only PsA patients, two specialised in FM enrolled only FM
patients, and one enrolled both PsA and FM patients. All of the patients were asked for
their informed consent to participate to the study.
Inclusion and exclusion criteria, and clinical evaluation
The inclusion criteria were a diagnosis of PsA or FM according to the CASPAR [6] and
1990 ACR criteria [3], and patient consent to participate. All of the consecutive adult
patients aged ≥18 years attending the clinics for routine examinations during the nine-
month study period who met the inclusion criteria were enrolled. They were all receiving
current standard levels of care for PsA and FM, and none was involved in any
interventional research protocol at the time. In addition, eligible FM patients could not have
a diagnosis or family history of PsA or psoriasis.
The study centres were provided with a paper or electronic case report form (CRF)
prepared by the coordinating centre (the Department of Rheumatology of the G. Pini
Orthopedic Institute in Milan) for anonymous data collection. The CRF included a patient
history, self-assessment questionnaires, and the findings of physical examinations and
laboratory investigations. The history included the time since the onset of the first
symptom, the familial and personal history of psoriasis, the presence of inflammatory back
pain (IBP) as defined by Calin’s criteria [7], the history of nine FM-related
conditions/symptoms (fatigue, headache, irritable bowel syndrome, sleep disturbances,
paresthesias, anxiety, depression, and Raynaud’s phenomenon) apparently not due to
other underlying conditions, and graded responsiveness (very good, good, slight and
Page 6 of 24
none) to non-steroidal anti-inflammatory drugs (NSAIDs). The questionnaires were the
Italian versions of the Disability Index of the Health Assessment Questionnaire (HAQ) [8],
the Fibromyalgia Impact Questionnaire (FIQ) [9], and the Leeds Disability Questionnaire
(LDQ) [10]. The patients were also asked to self-assess their pain and general health
using a 100-mm visual analogue scale (VAS). The physical examinations included routine
anthropometry, swollen and tender 66/68 joint counts, the number of irreversibly damaged
joints (defined as those with irreversible deformities and/or at least a 30% reduction in the
normal range of movement due to anatomic changes), pressure on the sacro-iliac joints to
elicit pain, tender point counts, the Maastricth Ankylosing Spondylitis Enthesitis Score
(MASES) [11], the number of digits with dactylitis, the Psoriasis Activity and Severity Index
(PASI) [12] for skin involvement, and the number of nails with psoriatic changes. The
pattern of articular involvement was established using the cumulative number of affected
joints, meaning all of the joints involved at the time of the study evaluation or documented
by a competent examiner on a previous occasion. The erythrocyte sedimentation rate
(ESR) (Westergren method) (n.v. <15 mm/h) and C-reactive protein (CRP) levels (n.v. <1
mg/dl) were the required laboratory tests. In order to reduce inter-observer variability in the
tender point and entheseal site examinations, a DVD was distributed to all of the centres
showing how to perform these examinations. We chose the MASES, rather than other
more comprehensive enthesitis scores, because it was the instrument all of the
investigators were most confident with. However, the following entheseal site was also
examined: lateral and medial epicondyles, greater trochanters, quadriceps tendons, and
plantar fascia insertions.
The enthesis involvement was also evaluated by ultrasonography (US) in a subgroup of 30
PsA and 30 FM patients, all from the coordinating centre. The Power Doppler Ultrasound
(PDUS) investigation was performed by a rheumatologist with extensive experience in US,
using a Logiq5 (General Electrics Medical Systems, Milwaukee, WI) machine equipped
Page 7 of 24
with a broadband high-frequency (8-15 MHz) transducer, and adopting a standardized
methodology [13]. The following entheseal sites were examined bilaterally: common
extensor tendon at its insertion at the lateral humeral epicondyle, gluteus tendon at their
insertion at the greater trochanter, quadriceps tendon at its insertion at the superior pole of
the patella, patellar tendon at its proximal insertion at the inferior pole of the patella,
patellar tendon at its distal insertion at the tibial tuberosity, Achilles tendon at its insertion
at the calcaneus, plantar aponeurosis at its insertion at the calcaneus. According to the
Outcome Measures in Rheumatology Clinical Trials (OMERACT) definitions of
enthesopathy, the following changes were registered [14]: tendon hypoechogenicity at its
bony insertion, tendon thickening at its bony insertion, intra-tendinous calcifications,
enthesophytes, bony erosions, bony cortex irregularities, presence of Doppler signal at the
bony insertion.
The coordinating centre collected the CRFs from all of the centres and controlled the
quality of the data (asking for clarifications of any missing or doubtful data), created the
final electronic database, cleaned the final data, and carried out the data analysis.
Statistical analysis
The descriptive statistics included the mean values and standard deviations (SD) of the
continuous variables, and the percentages and proportions of the categorical variables.
The univariate analyses were made using Student’s t test, the 2 test or Fisher’s exact test,
and Pearson's correlation test as appropriate. The multivariate logistic regression analysis
yielded the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the risk of
having FM rather than PsA for each variable.
As the primary study objective was to identify which of the clinical parameters of PsA were
more indicative of FM, only the FM-related features shared by both conditions were
analysed in greater detail. Accordingly, in the case of tender point counts, MASES scores
Page 8 of 24
and the presence of somatic symptoms (the most critical continuous variables
discriminating the two conditions), the most sensitive and specific cut-off points in favour of
FM were sought using receiver operating characteristic (ROC) curves. Similarly, the
multivariate analysis only considered the clinical manifestations common to both
conditions and most important for the differential diagnosis.
As the PsA patients belonging to the “enthesitis predominant” or oligoarticular subgroups
and those without psoriasis could be the most difficult to distinguish from FM, we analysed
them separately.
Given the small number of cases, no statistical analysis was performed for the PDUS data.
For all of the analyses, a p value of 0.05 was considered statistically significant. The data
were analysed using SPSS© software for Windows© (release 12.0, SPSS Inc., Chicago,
USA), version 17.0.
RESULTS
A total of 401 patients were enrolled but nine PsA patients were excluded because of
missing data and six FM patients because of the presence of dactylitis, a feature too much
indicative of SpA. Of the remaining 386 patients, 266 had PsA (125 females and 141
males) and 120 had FM (114 females and six males); the female/male ratio was 0.89 for
PsA and 19 for FM. Mean age at study entry was 51.7 years (SD 12.8) in the PsA group,
and 50.2 years (SD 10.7) in the FM group; the difference was not statistically significant.
Mean disease duration was 10.2 years (SD 9.3) in the PsA group, and 5.6 years (SD 4.5)
in the FM group. The differences in the gender ratios and disease duration were highly
significant (p <0.001) and inherent to the particular conditions. The mean body mass index
(BMI) was 27.1 (SD 6.1) in the PsA patients and 24.4 (SD 3.6) in the FM patients (p =
0.05). Finally, the 30 PsA (13 females and 17 males) and 30 FM patients (all females) of
the PDUS cohort had comparable mean age (51.612.2 and 51.211.6, respectively) and
BMI (25.25.3 and 24.93.7, respectively).
Table 1 shows the clinical characteristics of the study population. As laid down by the
protocol, none of the FM subjects had PsA or reported any personal or familial history of
psoriasis. The mean PASI of the PsA patients was only 2.2 (SD 3.1), indicating good
control of the skin disease. It is worth noting that 41 PsA patients (15.4%) had arthritis sine
psoriasis. The predominant pattern of articular involvement in the PsA group was
polyarthritis (150 patients, 56.8%), followed by oligoarthritis (67, 25.4%), axial involvement
(30, 11.4%), and enthesitis (17, 6.4%). Two patients had missing subgroup classification
data. Although almost 57% of the PsA patients were in the polyarthritis subset, the mean
number of (SD) of swollen joints was only 1.8 (3.5). This discrepancy was probably due to
the fact that virtually all of these patients were taking disease-modifying drugs and that
about 30% of them were on TNF- blockers.
Page 10 of 24
A number of the significant clinical differences between the two groups shown in Table 1
were expected and due to the intrinsic nature of the two diseases, but some were not. The
proportion of patients with IBP and tenderness in the sacroiliac joints upon examination
was similar in the two groups (about 35-40%), whereas the mean MASES was significantly
higher in the FM patients. One hundred and sixteen PsA patients (43.6%) reported a
“good” or “very good” response to NSAIDs therapy, against only 13 of the FM patients
(3.1%) (p<0.001).
About 40% of the PsA patients complained of extra-articular pain, but only 6.9% had at
least eleven tender points upon examination. All of the somatic manifestations were
significantly much more frequent in the FM patients, but as many as about 66% of the PsA
patients complained of fatigue.
As the MASES scores closely correlated with the tender point counts (r = 0.688, p<0.001),
we investigated whether any of the MASES sites were significantly more frequently
involved in one condition than the other. Univariate analysis showed that all of the sites
were significantly more frequently involved in FM, but only the seventh rib and the anterior
superior iliac spine remained significantly associated with FM at multivariate analysis (p
<0.001).
The PDUS evaluation showed inflammatory changes (tendon hypoechogenicity, bony
erosions, and PD signal in the enthesis) in 21 (70%) PsA patients but also in seven
(21.3%) FM patients. Bony erosions were the only findings absolutely specific for PsA, but
they were seen in only six (20%) patients. Ten entheseal sites per patient were examined
both clinically and by PDUS. This comparison yielded very different results in the two
conditions. Of the 300 examined sites in PsA patients, 25 were clinically positive and
PDUS negative, 39 clinically negative and PDUS positive, and 18 positive by both
methods. In FM patients, 112 sites were clinically positive and PDUS negative, 8 clinically
negative and PDUS positive, and only 4 positive by both methods. Interestingly enough, in
Page 11 of 24
these patients epicondyles and great trocanthers were responsible for almost all of clinical
entheseal involvement; only four Achilles tendons, five quadriceps tendons, and no plantar
fascia insertions were positive on clinical examination.
Given its efficacy in PsA, anti-tumour necrosis factor- (TNF) therapy may have been a
confounder in 33% of the PsA patients. However, as extra-articular pain was similarly
frequent in the patients on or off this therapy (44.9% and 39.6%), its impact on the clinical
findings could have been limited.
Table 2 shows the laboratory findings and the mean results of the questionnaires and
VAS. As expected, inflammatory indices were significantly higher in the PsA patients. The
mean FIQ values were significantly higher in the FM patients, whereas the mean values of
the two disability indices (HAQ and LDQ) were similar in the two groups.
As all of the somatic symptoms were significantly more frequent in the FM patients, we
used logistic regression analysis to establish which were independently predictive of FM.
The results showed that sleep disturbances, irritable bowel syndrome, Raynaud’s
phenomenon, and headache had the strongest ORs for FM (Tab. 3), whereas fatigue,
stiffness, depression and anxiety did not discriminate between PsA and FM.
The ROC curves (Fig. 1) showed that the most sensitive and specific predictors of a
diagnosis of FM was the presence of at least six somatic symptoms (sensitivity 93% and
specificity 82%) and at least eight tender points (sensitivity 93% and specificity 82%), and
a MASES score of 3 (sensitivity 68% and specificity 72%). The number of patients
satisfying the cut-off values derived from the ROC analysis of each variable was obviously
much higher in the FM group. However, 17.6% PsA patients had at least eight tender
points (as against 92.7% of FM patients), 14.1% had at least six FM-related symptoms (as
against 92.7% of FM patients), and 28.2% had a MASES score of 3 (as against 67.7% of
FM patients).
Page 12 of 24
The logistic regression model, which included all of the variables that were common to the
two conditions and most relevant to their differential diagnosis, showed that number of
somatic symptoms and number of tender points was independent predictors of FM (Table
4). Using the cut-off values identified by the ROC analysis the same model yielded an OR
of 14.73 (CI 3.61-60.09) for 6 somatic symptoms and 30.55 (CI 5.04-185.39) for 8
tender points,.
Finally, the analysis of the 17 patients of the “enthesitis predominant” subgroup, of the 67
with oligoarthritis, and of the 41 without psoriasis did not yield significant differences with
the PsA group as a whole, with the exception of “extra-articular pain”, which was more
frequent in the enthesitic subgroup (60% vs. 40.2%).
Page 13 of 24
DISCUSSION
The main aim of this study was to identify the clinical features that can help to distinguish
between PsA and FM.…